Cocaine is one of the major drugs of abuse in the U.S., and its use is still on the rise. The drug is taken for its strong central stimulant action, an effect that is believed to result from the interaction of cocaine with specific sites on nerve cells that are putatively termed "cocaine receptors." The long term objective of this research is to identify the physiologic role of the cocaine receptor in mammalian brain, to understand its structure and to determine what changes occur in numbers of receptors upon chronic cocaine administration. This would shed light on the causes of the reinforcing properties of cocaine or its addiction and hopefully suggest remedial or therapeutic actions. The specific aims are to identify the cocaine receptor in rat brain membranes, to purify it and to determine if repetitive cocaine administration causes changes in numbers of cocaine or other receptors. The hypothesis that the "cocaine receptor" is a catecholamine uptake carrier will be tested, and also whether it is the carrier for one or all biogenic amines. This will be achieved by correlating the potencies of cocaine analogs and other stimulants in displacing specific H-3-cocaine binding to brain synaptosomes with their potencies in inhibiting H-3-norepinephrine, H-3-dopamine and H-3-serotonin uptake by the synaptosomes. In addition, the "cocaine receptor(s)" will be purified by affinity chromatography using p-aminobenzyl cocaine as the immobilized adsorbing ligand; and purity of the isolated protein is checked with gel filtration and electrophoresis. Availability of the pure receptor will allow future studies on its structure, chemical nature and localization. The effects of repeated cocaine administration will be monitored on the numbers of receptors for cocaine, norepinephrine, dopamine and serotonin as well as biogenic amine carriers. Variations in densities of cocaine or other receptors would provide clues as to what factors may be involved in cocaine addiction and suggest possible therapy.